Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 222 (3), 271-80

Transplacental Arsenic Carcinogenesis in Mice

Affiliations

Transplacental Arsenic Carcinogenesis in Mice

Michael P Waalkes et al. Toxicol Appl Pharmacol.

Abstract

Our work has focused on the carcinogenic effects of in utero arsenic exposure in mice. Our data show that a short period of maternal exposure to inorganic arsenic in the drinking water is an effective, multi-tissue carcinogen in the adult offspring. These studies have been reproduced in three temporally separate studies using two different mouse strains. In these studies pregnant mice were treated with drinking water containing sodium arsenite at up to 85 ppm arsenic from days 8 to 18 of gestation, and the offspring were observed for up to 2 years. The doses used in all these studies were well tolerated by both the dam and offspring. In C3H mice, two separate studies show male offspring exposed to arsenic in utero developed liver carcinoma and adrenal cortical adenoma in a dose-related fashion during adulthood. Prenatally exposed female C3H offspring show dose-related increases in ovarian tumors and lung carcinoma and in proliferative lesions (tumors plus preneoplastic hyperplasia) of the uterus and oviduct. In addition, prenatal arsenic plus postnatal exposure to the tumor promoter, 12-O-tetradecanoyl phorbol-13-acetate (TPA) in C3H mice produces excess lung tumors in both sexes and liver tumors in females. Male CD1 mice treated with arsenic in utero develop tumors of the liver and adrenal and renal hyperplasia while females develop tumors of urogenital system, ovary, uterus and adrenal and hyperplasia of the oviduct. Additional postnatal treatment with diethylstilbestrol or tamoxifen after prenatal arsenic in CD1 mice induces urinary bladder transitional cell proliferative lesions, including carcinoma and papilloma, and enhances the carcinogenic response in the liver of both sexes. Overall this model has provided convincing evidence that arsenic is a transplacental carcinogen in mice with the ability to target tissues of potential human relevance, such as the urinary bladder, lung and liver. Transplacental carcinogenesis clearly occurs with other agents in humans and investigating a potential transplacental component of the human carcinogenic response to arsenic should be a research priority.

Figures

Fig. 1
Fig. 1
Hepatocellular carcinoma (HCC) incidence (left) and multiplicity (right) in adult male C3H mice exposed to arsenic in utero. The indicated maternal arsenic dose in the drinking water was given between gestation day 8 and 18 (see Methods for details). Incidence is the number of HCC bearing mice/number of mice available for examination. Multiplicity is defined as the average number of HCC per mouse and expressed as the mean ± SEM. An asterisk indicates a significant difference from control (p ≤ 0.05). Dose-related trend p values are shown. See Methods for specific statistical tests. Modified from Waalkes et al. (2003).
Fig. 2
Fig. 2
Transcript levels of ER-α and cyclin D1 in human liver from persons heavily exposed to environmental arsenic. Data are expressed as percent control with control set to 100% and expressed as mean ± SEM. An asterisk indicates a significant difference from control (p ≤ 0.05). Modified from Waalkes et al. (2004b).
Fig. 3
Fig. 3
Synergistic response in urogenital system carcinoma formation in adult female CD1 mice after combined in utero arsenic and postnatal DES. Pregnant mice received 85 ppm arsenic in the drinking water and the newborns were treated with DES on postnatal days 1, 2, 3, 4, and 5 (see Methods for experimental details). In this study, the urogenital system was considered to included the ovary, oviduct, uterus, cervix, vagina, kidney and urinary bladder. The arrow marked “Theoretical Additive” indicates the rate of urogenital carcinoma that occurs by simple addition of the rates in the arsenic alone and in the DES alone groups and should be compared to the synergistic increase seen in the group given the actual combination (Arsenic + DES group). Modified from Waalkes et al. (2006a).
Fig. 4
Fig. 4
Synergistic response in urinary bladder transitional cell proliferative lesions in adult female CD1 mice after combined in utero arsenic and postnatal DES. Pregnant mice received 85 ppm arsenic in the drinking water and the newborns were treated with DES on postnatal days 1, 2, 3, 4, and 5 (see Methods for experimental details). In this study, proliferative lesion incidence is defined as the incidence of combined transitional cell tumors and hyperplasia of the urinary bladder. Mice with multiple lesions of differing progression were considered as a single event. The hatched area in the Arsenic + DES group indicates the incidence of transitional cell carcinoma (TCC) that contributed to the overall incidence of proliferative lesions in this group. Modified from Waalkes et al. (2006a).
Fig. 5
Fig. 5
Synergistic response in urinary bladder transitional cell proliferative lesions and tumors in adult male CD1 mice after combined in utero arsenic and postnatal DES. Pregnant mice received 85 ppm arsenic in the drinking water and the newborns were treated with DES on postnatal days 1, 2, 3, 4, and 5 (see Methods for experimental details). In this study, proliferative lesion incidence is defined as the incidence of combined transitional cell tumors and hyperplasia of the urinary bladder. Mice with multiple lesions of differing progression were considered as a single event. Tumors included transitional cell papilloma and carcinoma. An asterisk indicates a significant difference from control (p ≤ 0.05). Modified from Waalkes et al. (2006b).

Similar articles

See all similar articles

Cited by 64 PubMed Central articles

See all "Cited by" articles

Publication types

MeSH terms

Feedback