Regular articleTransplacental carcinogenicity of inorganic arsenic in the drinking water: induction of hepatic, ovarian, pulmonary, and adrenal tumors in mice
Introduction
Inorganic arsenic is considered to be one of the highest priority hazardous substances in the United States. This is largely because of concern with the metalloid’s carcinogenic potential after environmental exposure Bates et al 1992, IARC 1987, Kitchin 2001, NRC 1999, Pott et al 2001, Simeonova and Luster 2000, Smith et al 1992. It is quite clear that exposure to inorganic arsenic in humans is etiologically linked to tumors of the skin, bladder, lung, liver, prostate, and possibly other tissues Bates et al 1992, IARC 1987, Kitchin 2001, NRC 1999, Pott et al 2001, Simeonova and Luster 2000, Smith et al 1992. In addition, many studies in human populations have shown clear dose–response relationships between environmental arsenic levels and cancer incidence Bates et al 1992, Kitchin 2001, NRC 1999, Pott et al 2001, Smith et al 1992.
The main source of environmental arsenic exposure in most populations is the drinking water, in which inorganic forms of arsenic predominate Bates et al 1992, NRC 1999, Pott et al 2001, Smith et al 1992. The inorganic forms of arsenic include the trivalent form, arsenite, and pentavalent form, arsenate. Clearly, assessing the risk from exposure to inorganic arsenic in water supplies is a key issue facing the scientific community. High levels of arsenic in the drinking water can be found in areas within many countries, including Taiwan, China, Chile, India, Mexico, and Bangladesh Bates et al 1992, NRC 1999, Pott et al 2001, Smith et al 1992, but it is becoming evident that even the more moderate levels of arsenic typically found in the United States may pose a significant health risk to humans Lewis et al 1999, Morales et al 2000. Indeed, studies in humans suggest that the risk posed by arsenic in the drinking water in the United States may be comparable to that from environmental tobacco or radon (Morales et al., 2000).
An important aspect of appropriately assigning the potential degree of hazard posed by a given level of exposure to any carcinogen is a knowledge of carcinogenic mechanisms, which helps to define appropriate models for risk assessment, particularly at lower levels of exposure. Generation of tumors in animals can be an invaluable aid in defining carcinogenic mechanisms. In this regard, while exposure to inorganic arsenic in humans is clearly carcinogenic IARC 1987, NRC 1999, carcinogenesis in animals resulting from exposure to inorganic arsenic, when given as a single agent, has been difficult to demonstrate convincingly Kitchin 2001, NRC 1999. Indeed, it is thought that the definition of the mechanism or mechanisms of arsenic carcinogenicity has been impeded by a lack of clear rodent models (Simeonova and Luster, 2000). However, there has been some very important recent progress made in the development of rodent models of inorganic arsenic carcinogenesis involving coexposure to other carcinogenic treatments Germolec et al 1997, Germolec et al 1998, Rossman et al 2001. This includes studies using Tg.AC (H-ras mutated) transgenic mice in which skin tumors are generated by co- exposure to arsenite in the drinking water and dermal application of 12-O-tetradecanoyl phorbol- 13-acetate (TPA; Germolec et al 1997, Germolec et al 1998. In addition, the incidence, multiplicity, and aggressiveness of tumors induced by ultraviolet radiation in the skin of hairless mice is markedly increased by inclusion of arsenite in the drinking water (Rossman et al., 2001). These mouse skin models Germolec et al 1997, Germolec et al 1998, Rossman et al 2001 represent very important advances and would point to copromotional or cocarcinogenic effects of oral inorganic arsenic, both of which could be important elements in dermal carcinogenicity of the metalloid, particularly as the skin is a human target site of arsenic carcinogenesis (NRC, 1999). Nonetheless, inorganic arsenic when given alone did not result in tumors of the skin or anywhere else in either of these two model systems Germolec et al 1997, Germolec et al 1998, Rossman et al 2001, and the requirement of coexposure to tumor-causing treatments (i.e., TPA or ultraviolet radiation) for tumor development to occur certainly complicates defining the precise contribution of arsenic in these treatment scenarios.
Inorganic arsenic is methylated in humans and most rodents, forming first a monomethylated and then a dimethylated (dimethylarsinic acid; DMA) compound Aposhian 1997, Kitchin 2001, NRC 1999, Thomas et al 2001. In this regard, a recent series of chronic carcinogenicity studies in rats with DMA Wei et al 1998, Wei et al 1999, Yamamoto et al 1995, Yamanaka et al 2000 has provided significant progress in our understanding of the carcinogenic potential of this methylated arsenic species (Kenyon and Hughes, 2001). For instance, DMA treatment can cause tumor promotion in the urinary bladder, liver, skin, and kidney in rats after initiation with a variety of potent organic carcinogens or by irradiation Wei et al 1998, Yamamoto et al 1995, Yamanaka et al 2000. Furthermore, long-term (∼2 years) exposure to DMA in the drinking water can act as a complete carcinogen in rats, inducing transition cell carcinoma and papilloma of the urinary bladder (Wei et al., 1999), a target tissue in humans (NRC, 1999). However, an issue with these studies is that, although DMA is generated from inorganic arsenic in humans and rodents, it is, of course, not the actual agent to which humans are exposed, since methylated species would rarely occur in drinking water (NRC, 1999). Clearly, whether chronic oral DMA exposure precisely duplicates the pharmacokinetics or toxic manifestations of chronic oral inorganic arsenic exposure in all its target tissues is an open question (Kenyon and Hughes, 2001). In addition, there are rat-specific, blood-borne arsenic-binding proteins that are absent in humans and other rodents, such as mice, that dramatically alter biokinetics and tissue dosimetry of both inorganic arsenic and DMA Kenyon and Hughes 2001, NRC 1999, Pott et al 2001.
Thus, although significant recent progress has been made, the development of rodent models of inorganic arsenic carcinogenesis clearly deserves additional attention. In this regard, gestation in rodents is often a period of high sensitivity to chemical carcinogenesis, with a variety of maternal exposures resulting in tumor formation in the offspring. This includes transplacental carcinogenesis induced by inorganics other than arsenic, such as lead (Waalkes et al., 1995), cisplatin Diwan et al 1993, Diwan et al 1995, and nickel (Diwan et al., 1992). There is at least one case report in humans in which maternal inorganic arsenic exposure from the therapeutic use of Fowler’s solution during pregnancy is suspected as a cause of multiple skin basaliomas (a typical form of skin cancer induced by arsenic) in a 32-year-old man (Aldick and Fabry, 1973). Arsenic appears to readily cross the human placenta, producing arsenic concentrations that are similar in cord blood compared to maternal blood (Concha et al., 1998). Arsenic given to maternal animals also moves readily across the placenta and substantial concentrations of arsenic have been measured in a variety of tissues in the embryo/fetus Lindgren et al 1984, NRC 1999. Significant transplacental transfer of arsenic occurs in all periods of gestation and after oral exposure in mice (NRC, 1999). Thus, the transplacental route is clearly a plausible mode of exposure in humans. Therefore, we performed a transplacental carcinogenicity study in mice in which pregnant animals were briefly exposed to well-tolerated levels of sodium arsenite in the drinking water and the offspring were subsequently examined for tumor development in adulthood. The results show that inorganic arsenic, as a single agent, induced tumors at multiple sites including the liver, adrenal, lung, and ovary after transplacental exposure and establishes inorganic arsenic as a complete transplacental carcinogen in mice.
Section snippets
Chemicals
Sodium arsenite (NaAsO2) was obtained from Sigma Chemical Co. (St. Louis, MO) and dissolved in sterile distilled water to the desired concentrations in the drinking water as parts per million arsenic.
Animals and treatments
Animal care was provided in accordance with the U.S. Public Health Policy on the Care and Use of Animals as defined in the Guide to the Care and Use of Animals (NIH publication No. 86-23). Mice were housed in a standard barrier facility, at a temperature of 68–72°F and with a relative humidity of
Results
Pregnant C3H mice were treated with 0 (control), 42.5, or 85 ppm arsenic as sodium arsenite in the drinking water from gestation days 8 to 18 and carcinogenic response was evaluated in the resulting offspring. Maternal drinking water consumption was not altered by the inclusion of arsenic in the drinking water. For instance, on the last day of treatment (gestation day 18) control mice consumed 9.08 ± 0.25 ml per mouse (n = 5; mean ± SE) compared to 8.86 ± 0.27 and 8.72 ± 0.27 ml per mouse in
Discussion
The present results show that exposure of pregnant C3H mice to inorganic arsenic through the drinking water at well-tolerated levels in the later stage of gestation induces a variety of tumors in the resulting offspring. This includes aggressive epithelial malignancies, such as hepatocellular carcinoma and pulmonary adenocarcinoma, that occurred in the absence of any treatment other than inorganic arsenic. Both the liver and lung are target sites of carcinogenesis in humans after oral exposure
Acknowledgements
The authors thank Dan Logsdon, Keith Rodgers, Barbara Kasprzak, and Jeannie Herring for technical assistance and William Achanzar and Larry Keefer for critically reviewing this manuscript. Research was funded in part by the National Cancer Institute under Contract no. NO1-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products, or organizations imply
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