Arsenic Exposure In Utero and Nonepidermal Proliferative Response in Adulthood in Tg.AC Mice

National Cancer Institute at NIEHS, Research Triangle Park, NC 27709, USA.
International Journal of Toxicology (Impact Factor: 1.29). 05/2010; 29(3):291-6. DOI: 10.1177/1091581810362804
Source: PubMed


To expand our knowledge on the transplacental carcinogenic potential of inorganic arsenic, pregnant Tg.AC mice received drinking water with 0, 42.5, or 85 ppm arsenite from gestation day 8 to 18. After birth, groups (n = 25) of offspring received topical 12-O-tetradecanoyl phorbol-13-acetate (TPA) (2 microg twice a week) for 36 weeks and were killed; nonskin tumors were assessed. Arsenic increased adrenal cortical adenomas (ACAs; 25%-29%) compared with control (0%) independent of TPA in all male groups. Arsenic increased urinary bladder (UB) hyperplasia in males, but only with TPA. Arsenic induced ACAs in all female groups (control 0%; arsenic 17%-26%). Arsenic-treated females had UB hyperplasia in most groups (control 0%; arsenic 26%-32%), with 2 UB papillomas. All arsenic-treated females had uterine hyperplasia (26%-40%; control 4%) independent of TPA, and 3 had uterine tumors. Thus, arsenic in utero rapidly induces ACAs and uterine and UB preneoplasias in Tg.AC mice, showing transplacental carcinogenic potential in yet another strain of mice.

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    • "Discussion Most of the animal studies on the health impact of arsenic exposures focus primarily on the high doses (ppm level) with exposure period in the adulthood. Analyses of arsenic exposure during fetal life indicate that the exposed mice are more susceptible to tumors than controls (Tokar et al. 2010; Waalkes et al. 2004a; Waalkes et al. 2006; Waalkes et al. 2007). However, the consequence of exposure on other physiological functions remains unclear. "
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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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    • "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.
    Preview · Article · Mar 2012 · Toxicology Letters
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    • "However, for environmental carcinogens, it is likely that humans would have full life exposure. Our transplacental studies use maternal oral treatment with inorganic arsenic (42.5 and 85 ppm) from gestation days 8 to 18, and although showing consistent carcinogenic activity in the offspring as adults (Tokar et al., 2010a; Waalkes et al., 2003, 2004b, 2006a,b), this protocol does not duplicate typical human exposure. Arsenic has a very short biological half-life (~5 days), and with these protocols, arsenic would be rapidly gone from the newborn. "
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    ABSTRACT: In a previously developed mouse model, arsenic exposure in utero induces tumors at multiple sites in the offspring as adults, often duplicating human targets. However, human environmental inorganic arsenic exposure occurs during the entire life span, not just part of gestation. Thus, "whole-life" inorganic arsenic carcinogenesis in mice was studied. CD1 mice were exposed to 0, 6, 12, or 24 ppm arsenic in the drinking water 2 weeks prior to breeding, during pregnancy, lactation, and after weaning through adulthood. Tumors were assessed in offspring until 2 years of age. Arsenic induced dose-related increases in lung adenocarcinoma (both sexes), hepatocellular carcinoma (both sexes), gallbladder tumors (males), and uterine carcinomas. Arsenic induced dose-related increases in ovarian tumors (including carcinomas) starting with the lowest dose. Adrenal tumors increased at all doses (both sexes). Arsenic-induced lung and liver cancers were highly enriched for cancer stem cells, consistent with prior work with skin cancers stimulated by prenatal arsenic. Reproductive tract tumors overexpressed cyclooxygenase-2 and estrogen receptor-α. Arsenic target sites were remarkably similar to prior transplacental studies, although tumors from whole-life exposure were generally more aggressive and frequent. This may indicate that arsenic-induced events in utero dictate target site in some tissues, whereas other exposure periods of arsenic enhance incidence or progression, though other factors could be at play, like cumulative dose. Whole-life arsenic exposure induced tumors at dramatically lower external doses than in utero arsenic only while more realistically duplicating human exposure.
    Full-text · Article · Oct 2010 · Toxicological Sciences
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