Impact of life stage and duration of exposure on arsenic-induced proliferative lesions and neoplasia in C3H mice

Abstract

Epidemiological studies suggest that chronic exposure to inorganic arsenic is associated with cancer of the skin, urinary bladder and lung as well as the kidney and liver. Previous experimental studies have demonstrated increased incidence of liver, lung, ovary, and uterine tumors in mice exposed to 85 ppm (∼8 mg/kg) inorganic arsenic during gestation. To further characterize age susceptibility to arsenic carcinogenesis we administered 85 ppm inorganic arsenic in drinking water to C3H mice during gestation, prior to pubescence and post-pubescence to compare proliferative lesion and tumor outcomes over a one-year exposure period. Inorganic arsenic significantly increased the incidence of hyperplasia in urinary bladder (48%) and oviduct (36%) in female mice exposed prior to pubescence (beginning on postnatal day 21 and extending through one year) compared to control mice (19 and 5%, respectively). Arsenic also increased the incidence of hyperplasia in urinary bladder (28%) of female mice continuously exposed to arsenic (beginning on gestation day 8 and extending though one year) compared to gestation only exposed mice (0%). In contrast, inorganic arsenic significantly decreased the incidence of tumors in liver (0%) and adrenal glands (0%) of male mice continuously exposed from gestation through one year, as compared to levels in control (30 and 65%, respectively) and gestation only (33 and 55%, respectively) exposed mice. Together, these results suggest that continuous inorganic arsenic exposure at 85 ppm from gestation through one year increases the incidence and severity of urogenital proliferative lesions in female mice and decreases the incidence of liver and adrenal tumors in male mice. The paradoxical nature of these effects may be related to altered lipid metabolism, the effective dose in each target organ, and/or the shorter one-year observational period.

Chronic exposure to arsenic in drinking water can lead to resistance to antimonial drugs in a mouse model of visceral leishmaniasis

“…Levels between 0.4 and 1.5 mg per kg wet weight were seen in the livers of BALB/c mice exposed to arsenic at 100 ppm throughout the arsenic exposure time course (days 7, 14, 28, and 56). These experimental results are comparable to those found with similar exposures in C3H mice in the literature (14,15). Fig.…”

In utero arsenic exposure in mice and early life susceptibility to cancer

“…In another study in which arsenite was administered in the drinking water to mice (Suzuki et al, 2008), 100 ppm sodium arsenite was associated with a 26e44% reduction in water consumption; reductions in food consumption were also seen in female, but not male, mice. Further, among the studies being assessed herein, Ahlborn et al (2009) reported that water consumption was significantly reduced (by 40%) in F1 male and female offspring on PND 32 when these animals were being acclimated to arsenite in the drinking water; however, this effect was reported to have disappeared by two months of age (Ahlborn et al, 2009). Although maternal water consumption was reported to be unaffected by arsenite exposure, these data were collected on a bimonthly basis, which may have been too infrequent to detect effects, especially at the beginning of the exposure period.…”

“…All of the NIEHS studies were conducted at the National Cancer Institute's Frederick, MD animal facility. Ahlborn et al (2009) conducted a similar study that included an in utero-only exposure group, in addition to groups with longer exposure durations during later life-stages. In some cases the mice also received co-exposures and/or administration of different forms of arsenic.…”

“…In a study conducted at the U.S. Environmental Protection Agency laboratories in Research Triangle Park, NC, Ahlborn and colleagues (Ahlborn et al, 2009;Nelson et al, 2009) evaluated the age susceptibility suggested by the data from NIEHS. C3H mice were administered 0 or 85 ppm sodium arsenite in drinking water by one of the following regimens: in utero-only (GD 8-18), continuously from in utero through one year of age (GD 8 to postnatal day [PND] 365), pre-pubescence through one year of age (PND 21-365), or post-pubescence through one year of age (PND 56-365).…”

“…This would have been a potentially plausible explanation if the in utero group and continuous exposure group (which included both in utero and pre-pubescent exposures) had also induced hyperplasia. If postnatal iAs exposure is indeed protective for mice, even after in utero exposure to iAs, as data from Ahlborn et al (2009) suggest, it raises questions about the relevance of in utero-only exposure studies since this would be an unlikely exposure pattern for humans. Nohara et al (2012) adapted the NIEHS transplacental carcinogenesis protocol to evaluate potential mechanisms of liver carcinogenesis in C3H mice, which have a high rate of spontaneous liver tumors.…”