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.

Arsenic is a recognized human carcinogen and development of rodent models remains a critically important research objective. Since gestation can be a period of high sensitivity to chemical carcinogenesis, we have performed a series of transplacental carcinogenicity studies in mice with inorganic arsenic. In this study, groups of pregnant C3H mice received drinking water containing sodium arsenite (NaAsO2) at 0, 42.5 and 85 p.p.m. arsenic ad libitum from days 8 to 18 of gestation. These doses of arsenic were well tolerated. Dams delivered normally and at weaning (4 weeks) offspring were randomly put into groups (n = 25) of males or females according to maternal dose. In an attempt to promote skin cancers initiated by transplacental arsenic, duplicate groups of control or arsenic exposed offspring were topically exposed to 12-O-tetradecanoyl phorbol-13-acetate (TPA; 2 micro g/0.1 ml acetone, twice/week) from 4 to 25 weeks of age. Irrespective of TPA exposure, male offspring showed arsenic-induced dose-related increases in hepatocellular carcinoma incidence and multiplicity, as well as increases in adrenal tumor incidence and multiplicity. In female offspring, an increase in epithelial ovarian tumors occurred with arsenic exposure regardless of TPA exposure. Females also showed pre-neoplastic lesions of the reproductive tract, including hyperplasia of the uterus and oviduct, after arsenic but independent of TPA exposure. Although TPA had no effect on skin tumors, it promoted arsenic initiated liver tumors in females and lung tumors in both sexes. Thus, inorganic arsenic, as a single agent, can consistently act as a complete transplacental carcinogen in mice, inducing tumors at multiple sites, and as a tumor initiator in some tissues. Skin tumors were not initiated by arsenic in mouse fetuses possibly indicating tissue-specific mechanisms of action. This study indicates that gestation is a period of high sensitivity to arsenic carcinogenesis.

[1]  B. Danielsson,et al.  Embryotoxicity of arsenite and arsenate: distribution in pregnant mice and monkeys and effects on embryonic cells in vitro. , 2009, Acta pharmacologica et toxicologica.

[2]  S. Fukushima,et al.  Carcinogenicity of dimethylarsinic acid in p53 heterozygous knockout and wild-type C57BL/6J mice. , 2003, Carcinogenesis.

[3]  M. Webber,et al.  Inorganic arsenite-induced malignant transformation of human prostate epithelial cells. , 2002, Journal of the National Cancer Institute.

[4]  I. Jaspers,et al.  The role of biomethylation in toxicity and carcinogenicity of arsenic: a research update. , 2002, Environmental health perspectives.

[5]  F. Mullick,et al.  Pathology related to chronic arsenic exposure. , 2002, Environmental health perspectives.

[6]  S. Fukushima,et al.  Carcinogenicity of dimethylarsinic acid in male F344 rats and genetic alterations in induced urinary bladder tumors. , 2002, Carcinogenesis.

[7]  Shan Lin,et al.  The cellular metabolism and systemic toxicity of arsenic. , 2001, Toxicology and applied pharmacology.

[8]  T. Rossman,et al.  Arsenite is a cocarcinogen with solar ultraviolet radiation for mouse skin: an animal model for arsenic carcinogenesis. , 2001, Toxicology and applied pharmacology.

[9]  K. Kitchin.  Recent advances in arsenic carcinogenesis: modes of action, animal model systems, and methylated arsenic metabolites. , 2001, Toxicology and applied pharmacology.

[10]  S. Okada,et al.  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. , 2001, Biological & pharmaceutical bulletin.

[11]  A. Giri,et al.  Genetic toxicology of a paradoxical human carcinogen, arsenic: a review. , 2001, Mutation research.

[12]  W. Cullen,et al.  Differential effects of trivalent and pentavalent arsenicals on cell proliferation and cytokine secretion in normal human epidermal keratinocytes. , 2001, Toxicology and applied pharmacology.

[13]  E. Kenyon,et al.  A concise review of the toxicity and carcinogenicity of dimethylarsinic acid. , 2001, Toxicology.

[14]  W. Cullen,et al.  Methylated trivalent arsenic species are genotoxic. , 2001, Chemical research in toxicology.

[15]  J. Sawicki,et al.  K6/ODC transgenic mice as a sensitive model for carcinogen identification. , 2000, Toxicology letters.

[16]  L. Keefer,et al.  Induction of proliferative lesions of the uterus, testes, and liver in swiss mice given repeated injections of sodium arsenate: possible estrogenic mode of action. , 2000, Toxicology and applied pharmacology.

[17]  L. Ryan,et al.  Risk of internal cancers from arsenic in drinking water. , 2000, Environmental health perspectives.

[18]  S. Fukushima,et al.  Promotion of Skin Carcinogenesis by Dimethylarsinic Acid in Keratin (K6)/ODC Transgenic Mice , 2000, Japanese journal of cancer research : Gann.

[19]  L. Anderson,et al.  Critical windows of exposure for children's health: cancer in human epidemiological studies and neoplasms in experimental animal models. , 2000, Environmental health perspectives.

[20]  S. Okada,et al.  The role of orally administered dimethylarsinic acid, a main metabolite of inorganic arsenics, in the promotion and progression of UVB-induced skin tumorigenesis in hairless mice. , 2000, Cancer letters.

[21]  E. Kenyon,et al.  Strain-dependent disposition of inorganic arsenic in the mouse. , 1999, Toxicology.

[22]  Wei Li,et al.  Urinary bladder carcinogenicity of dimethylarsinic acid in male F344 rats. , 1999, Carcinogenesis.

[23]  J. DiGiovanni,et al.  Genetics of skin tumor promotion. , 1999, Progress in experimental tumor research.

[24]  D. R. Lewis,et al.  Drinking water arsenic in Utah: A cohort mortality study. , 1999, Environmental health perspectives.

[25]  Wei Li,et al.  Promotion of NCI-Black-Reiter male rat bladder carcinogenesis by dimethylarsinic acid an organic arsenic compound. , 1998, Cancer letters.

[26]  J. Spalding,et al.  Arsenic enhancement of skin neoplasia by chronic stimulation of growth factors. , 1998, The American journal of pathology.

[27]  M. Vahter,et al.  Exposure to inorganic arsenic metabolites during early human development. , 1998, Toxicological sciences : an official journal of the Society of Toxicology.

[28]  Chien-Jen Chen,et al.  Epidemiological characteristics and risk factors of hepatocellular carcinoma , 1997, Journal of gastroenterology and hepatology.

[29]  B. Diwan,et al.  Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[30]  R. Tennant,et al.  Arsenic can mediate skin neoplasia by chronic stimulation of keratinocyte-derived growth factors. , 1997, Mutation research.

[31]  J. Ward,et al.  Renal tubular tumors and atypical hyperplasias in B6C3F1 mice exposed to lead acetate during gestation and lactation occur with minimal chronic nephropathy. , 1995, Cancer research.

[32]  J. Ward,et al.  Transplacental carcinogenesis by cisplatin in F344/NCr rats: promotion of kidney tumors by postnatal administration of sodium barbital. , 1995, Toxicology and Applied Pharmacology.

[33]  S. Fukushima,et al.  Cancer induction by an organic arsenic compound, dimethylarsinic acid (cacodylic acid), in F344/DuCrj rats after pretreatment with five carcinogens. , 1995, Cancer research.

[34]  L. Anderson,et al.  Transplacental carcinogenicity of cisplatin: initiation of skin tumors and induction of other preneoplastic and neoplastic lesions in SENCAR mice. , 1993, Cancer research.

[35]  B. Diwan,et al.  Transplacental carcinogenic effects of nickel(II) acetate in the renal cortex, renal pelvis and adenohypophysis in F344/NCr rats. , 1992, Carcinogenesis.

[36]  A. Smith,et al.  Cancer risks from arsenic in drinking water. , 1992, Environmental health perspectives.

[37]  A. Smith,et al.  Arsenic ingestion and internal cancers: a review. , 1992, American journal of epidemiology.

[38]  C. J. Chen,et al.  Ecological correlation between arsenic level in well water and age-adjusted mortality from malignant neoplasms. , 1990, Cancer research.

[39]  C. Chen,et al.  Dose-response relation between arsenic concentration in well water and mortality from cancers and vascular diseases. , 1989, American journal of epidemiology.

[40]  K. Goerttler,et al.  Diaplacental carcinogenesis: Tumor localization and tumor incidence in NMRI mice after diaplacental initiation with DMBA and urethane and postnatal promotion with the phorbol ester TPA in a modified 2-stage Berenblum/Mottram experiment , 1977, Virchows Archiv A.

[41]  I. Berenblum,et al.  Possible two‐stage transplacental liver carcinogenesis in c57bl/6 mice , 1977, International journal of cancer.

[42]  I. Berenblum,et al.  Systemic promoting action of phorbol in liver and lung carcinogenesis in AKR mice. , 1972, Cancer research.

[43]  J. Ward,et al.  Transplacental carcinogenicity of inorganic arsenic in the drinking water: induction of hepatic, ovarian, pulmonary, and adrenal tumors in mice. , 2003, Toxicology and applied pharmacology.

[44]  R. S. Yang,et al.  Pharmacokinetics, metabolism, and carcinogenicity of arsenic. , 2001, Reviews of environmental contamination and toxicology.

[45]  M. Luster,et al.  Mechanisms of arsenic carcinogenicity: genetic or epigenetic mechanisms? , 2000, Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer.

[46]  H. Aposhian.  Enzymatic methylation of arsenic species and other new approaches to arsenic toxicity. , 1997, Annual review of pharmacology and toxicology.

[47]  E. Somers.  International Agency for Research on Cancer. , 1985, CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne.

[48]  K. Goerttler,et al.  Diaplacental initiation of NMRI mice with 7,12-dimethylbenz[a]anthracene during gestation days 6--20 and postnatal treatment of the F1-generation with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate: tumor incidence in organs other than the skin. , 1981, Carcinogenesis.