Urogenital carcinogenesis in female CD1 mice induced by in utero arsenic exposure is exacerbated by postnatal diethylstilbestrol treatment

Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at National Institute of Environmental Health Sciences, PO Box 12233, 111 Alexander Drive, Research Triangle Park, NC 27709, USA.
Cancer Research (Impact Factor: 9.28). 03/2006; 66(3):1337-45. DOI: 10.1158/0008-5472.CAN-05-3530
Source: PubMed

ABSTRACT Transplacental inorganic arsenic carcinogenicity, together with postnatal exposure to diethylstilbestrol or tamoxifen, was studied. Pregnant CD1 mice received 85 ppm arsenic in the drinking water from gestation days 8 to 18 and were allowed to give birth. Groups (n = 35) of female offspring were injected s.c. on postpartum days 1 through 5 with diethylstilbestrol (2 microg/pup/d) or tamoxifen (10 microg/pup/d) and observed for 90 weeks. Arsenic alone induced some urogenital system tumors, including mostly benign tumors of the ovary and uterus, and adrenal adenoma. Diethylstilbestrol alone induced some tumors (primarily cervical) but when given after in utero arsenic, it greatly enhanced urogenital tumor incidence, multiplicity, and progression. For instance, compared with the incidence of urogenital malignancies in the control (0%), arsenic alone (9%), and diethylstilbestrol alone (21%) groups, arsenic plus diethylstilbestrol acted synergistically, inducing a 48% incidence of malignant urogenital tumors. Of the urogenital tumors induced by arsenic plus diethylstilbestrol, 80% were malignant, and 55% were multiple site. Arsenic plus diethylstilbestrol increased ovarian, uterine, and vaginal tumors, and urinary bladder proliferative lesions, including three transitional cell carcinomas. Tamoxifen alone did not increase urogenital tumors or affect arsenic-induced neoplasia but did increase arsenic-induced uroepithelial proliferative lesions. Uterine and bladder carcinoma induced by arsenic plus diethylstilbestrol greatly overexpressed estrogen receptor-alpha (ER-alpha) and pS2, an estrogen-regulated gene. In neonatal uteri, prenatal arsenic increased ER-alpha expression and enhanced estrogen-related gene expression induced by postnatal diethylstilbestrol. Thus, arsenic acts with estrogens to enhance production of female mouse urogenital cancers.

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    • "Prior studies failed to detect ERα as a key player in BBN-induced bladder carcinogenesis in mice or rats [56] [57] [63]; instead, they identified pathways such as those involving epidermal growth factor receptor–Ras, cell cycle, transforming growth factor–β, c-Myc, apoptosis, and integrin-mediated cell adhesion in BBN-induced carcinogenesis. However, in a very different model of bladder cancer in which female mice are exposed to inorganic arsenic in utero followed by postnatal diethylstilbestrol, the resulting bladder transitional cell carcinomas are positive for ERα [64], raising the possibility that expression of this receptor may contribute to a cancer phenotype. The role of ERα as a positive regulator of proliferation and its association with inflammatory responses and the development of malignancy are well established [41]. "
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    ABSTRACT: Bladder cancer is the fifth most frequent tumor in men and ninth in women in the United States. Due to a high likelihood of recurrence, effective chemoprevention is a significant unmet need. Estrogen receptors (ERs), primarily ERβ, are expressed in normal urothelium and urothelial carcinoma, and blocking ER function with selective ER modulators such as tamoxifen inhibits bladder cancer cell proliferation in vitro. Herein, the chemoprotective potential of tamoxifen was evaluated in female mice exposed to the bladder-specific carcinogen, N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). Carcinogen treatment resulted in a 76% tumor incidence and increased mean bladder weights in comparison to controls. In contrast, mice receiving tamoxifen concurrent (8–20 weeks) or concurrent and subsequent (8–32 weeks) to BBN administration had no change in bladder weight and only 10% to 14% incidence of tumors. Non–muscle-invasive disease was present in animals treated with tamoxifen before (5–8 weeks) or after (20–32 weeks) BBN exposure, while incidence of muscle-invasive bladder carcinoma was reduced. ERβ was present in all mice and thus is a potential mediator of the tamoxifen chemoprotective effect. Surprisingly, ERα expression, which was detected in 74% of the mice exposed to BBN alone but not in any controlmice, was correlated with tumor incidence, indicating a possible role for this receptor in carcinogen-induced urothelial tumorigenesis. Thus, these data argue that both ERα and ERβ play a role in modulating carcinogen-induced bladder tumorigenesis. Administration of tamoxifen should be tested as a chemopreventive strategy for patients at high risk for bladder cancer recurrence.
    Translational oncology 06/2013; 6(6):244-255. DOI:10.1593/tlo.13247 · 3.40 Impact Factor
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    • "It is of interest that perinatal exposure of CD1 mice to diethylstilbestrol can also induce rete testis or interstitial cell proliferative lesions including tumors (Newbold et al. 1985, 1987). In this regard, diethylstilbestrol is also able to promote lesions initiated by prenatal exposure to inorganic arsenic into tumors in various tissues, including several sites within the female reproductive tract (Waalkes et al. 2006b) and in the male liver (Waalkes et al. 2006a) although this was not observed in the testes. Prenatal inorganic arsenic exposure activates estrogen receptors in various tissues (Shen et al. 2007; Waalkes et al. 2004b, 2006a, 2006b), however, the role of estrogen receptor activation in the pathogenesis of cancer resulting from early life inorganic arsenic or MMA3+ exposure is not fully understood. "
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    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.
    Archives of Toxicology 03/2012; 86(6):975-82. DOI:10.1007/s00204-012-0820-8 · 5.08 Impact Factor
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    • "DMA is also a urinary bladder carcinogen by itself in adult rats (Arnold et al., 2006; Wei et al., 1999, 2002), but has not been shown to be similarly effective in adult mice (IARC 2004, 2009; Tokar et al., 2010a, b, 2011). Maternal exposure to inorganic arsenic in the drinking water during gestation in several strains of mice results in a significant level of urinary bladder hyperplasia in the offspring during adulthood (Tokar et al., 2010a; Waalkes et al., 2006a,b), including CD1 mice (Waalkes et al., 2006a,b), which can be promoted to advanced tumors by other treatments (Waalkes et al., 2006a,b). Chronic oral exposure to DMA in the drinking water will also act as a bladder tumor promoter in rats after treatment with low level organic carcinogens (Wanibuchi et al., 1996; Yamamoto et al., 1995). "
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    ABSTRACT: Inorganic arsenic, an early life carcinogen in humans and mice, can initiate lesions promotable by other agents in later life. The biomethylation product of arsenic, dimethylarsinic acid (DMA), is a multi-site tumor promoter. Thus, pregnant CD1 mice were given drinking water (0 ppm or 85 ppm arsenic) from gestation day 8 to 18 and after weaning male offspring received DMA (0 ppm or 200 ppm; drinking water) for up to 2 years. No renal tumors occurred in controls or DMA alone treated mice while gestational arsenic exposure plus later DMA induced a significant renal tumor incidence of 17% (primarily renal cell carcinoma). Arsenic plus DMA or arsenic alone also increased renal hyperplasia over control but DMA alone did not. Arsenic alone, DMA alone and arsenic plus DMA all induced urinary bladder hyperplasia (33-35%) versus control (2%). Compared to control (6%), arsenic alone tripled hepatocellular carcinoma (20%), and arsenic plus DMA doubled this rate again (43%), but DMA alone had no effect. DMA alone, arsenic alone, and arsenic plus DMA increased lung adenocarcinomas and adrenal adenomas versus control. Overall, DMA in adulthood promoted tumors/lesions initiated by prenatal arsenic in the kidney and liver, but acted independently in the urinary bladder, lung and adrenal.
    Toxicology Letters 03/2012; 209(2):179-85. DOI:10.1016/j.toxlet.2011.12.016 · 3.36 Impact Factor
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