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: 9.33). 03/2006; 66(3):1337-45. DOI: 10.1158/0008-5472.CAN-05-3530
Source: PubMed


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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    • "In mice, in utero exposure to arsenic (in doses ranging from 42.5 ppm to 85 ppm) resulted in an increased incidence of lung, liver, adrenal, skin and ovarian tumors when the exposed embryos reach adulthood (Liu et al. 2007; Tokar et al. 2010; Waalkes et al. 2004b). The urogenital system is a known target tissue for arsenic toxicity as CD-1 mice exposed to arsenic at 85 ppm in utero from embryonic day or E8 to 18 exhibited increased incidence of ovary, uterus and adrenal gland tumors at 90 weeks of age (Waalkes et al. 2006). "
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    ABSTRACT: Mice exposed to high levels of arsenic in utero are more susceptible to tumors such as hepatic and pulmonary carcinoma when they reach adulthood. However, effects of in utero arsenic exposure on general physiological functions such as reproduction and metabolism remain unclear. We evaluated the effect of in utero exposure to inorganic arsenic at the EPA drinking water standard (10 ppb) and tumor-inducing level (42.5 ppm) on reproductive end points and metabolic parameters when the exposed females reach adulthood. Pregnant CD-1 mice were exposed to sodium arsenite (0, 10 ppb, or 42.5 ppm) in drinking water from gestational day 10 to birth, the window of organ formation. At birth, exposed offspring were fostered to unexposed dams. We examined reproductive end points (age at vaginal opening, reproductive hormone levels, estrous cyclicity, and fertility) and metabolic parameters (body weight changes, hormone levels, body fat content, and glucose tolerance) of the exposed females in adulthood. Arsenic-exposed females (10 ppb and 42.5 ppm) exhibited early onset of vaginal opening. Fertility was not affected when females were exposed to the 10 ppb dose. However, the number of litters per female was decreased in females exposed to 42.5 ppm of arsenic in utero. In both 10 ppb and 42.5 ppm groups, exposed females had significantly higher body weight gain, body fat content, and glucose intolerance. Our findings reveal unexpected effects that in utero exposure to arsenic at a human relevant low dose and a tumor-inducing level leads to early onset of vaginal opening and obesity in female CD-1 mice.
    Full-text · Article · Aug 2015 · Environmental Health Perspectives
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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.
    Full-text · Article · Jun 2013 · Translational oncology
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    • "Epidemiological evidence links in utero and early-life human exposures to arsenic with increased risk of cancer mortality during early adulthood [18-20], as well as with developmental and long-term health consequences, including pulmonary and cardiovasuclar diseases, fetal loss and birth defects [21]. In an experimental animal study, in utero exposure to inorganic arsenic resulted in a variety of tumors in the off-spring when they reached adulthood [22-24]. Additionally, it has been proposed that gestational disruption of normal epigenetic programming by arsenic may lead to aberrant gene expression, which in turn influences fetal development and disease risk later in life [25]. "
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    ABSTRACT: BACKGROUND: Accumulating evidence indicates that in utero exposure to arsenic is associated with congenital defects and long-term disease consequences including cancers. Recent studies suggest that arsenic carcinogenesis results from epigenetic changes, particularly in DNA methylation. This study aimed to investigate DNA methylation changes as a result of arsenic exposure in utero and in vitro. METHODS: For the exposure in utero study, a total of seventy-one newborns (fifty-five arsenic-exposed and sixteen unexposed newborns) were recruited. Arsenic concentrations in the drinking water were measured, and exposure in newborns was assessed by measurement of arsenic concentrations in cord blood, nails and hair by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). In the in vitro study, human lymphoblasts were treated with arsenite at 0-100 muM for two, four and eight hours (short-term) and at 0, 0.5 and 1.0 muM for eight-weeks period (long-term). DNA methylation was analyzed in cord blood lymphocytes and lymphoblasts treated with arsenite in vitro. Global DNA methylation was determined as LINE-1 methylation using combined bisulfite restriction analysis (COBRA) and total 5-methyldeoxycytidine (5MedC) content which was determined by HPLC-MS/MS. Methylation of p53 was determined at the promoter region using methylation-specific restriction endonuclease digestion with MspI and HpaII. RESULTS: Results showed that arsenic-exposed newborns had significantly higher levels of arsenic in cord blood, fingernails, toenails and hair than those of the unexposed subjects and a slight increase in promoter methylation of p53 in cord blood lymphocytes which significantly correlated with arsenic accumulation in nails (p < 0.05) was observed, while LINE-1 methylation was unchanged. Short-term in vitro arsenite treatment in lymphoblastoid cells clearly demonstrated a significant global hypomethylation, determined as reduction in LINE-1 methylation and total 5-MedC content, and p53 hypermethylation (p < 0.05). However, a slight LINE-1 hypomethylation and transient p53 promoter hypermethylation were observed following long-term in vitro treatment. CONCLUSIONS: This study provides an important finding that in utero arsenic exposure affects DNA methylation, particularly at the p53 promoter region, which may be linked to the mechanism of arsenic carcinogenesis and the observed increased incidence of cancer later in life.
    Full-text · Article · May 2012 · Environmental Health
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