EPA Science Inventory

Impact of life stage and duration of exposure on arsenic-induced proliferative lesions, neoplasia, and gene expression in male C3H mice.

Citation:

NELSON, GAIL M., G. AHLBORN, D. A. DELKER, H. REN, K. T. KITCHIN, C. CORTON, D. Waalkes, D. Diwan, AND J. W. ALLEN. Impact of life stage and duration of exposure on arsenic-induced proliferative lesions, neoplasia, and gene expression in male C3H mice. Presented at Society of Toxicology Annual Meeting, Baltimore, MD, March 15 - 19, 2009.

Description:

Previous studies have demonstrated increased liver and adrenal tumor incidence in male mice exposed gestationally to 85 ppm inorganic arsenic via the dams’ drinking water. To further characterize age susceptibility to arsenic carcinogenesis we have administered 85 ppm sodium arsenite to C3H mice during gestation, prior to pubescence, and post-pubescence to compare proliferative lesions, tumor outcomes, and global liver gene expression patterns after one year. Incidence of urinary bladder hyperplasia was increased in continuously exposed mice compared to in utero only exposed mice. In contrast, the incidence of liver and adrenal tumors in male mice continuously in utero only exposed mice. This apparent protective effect of continuous arsenic exposure was accompanied by expression changes for many genes known to be involved in liver cancer including cell growth and proliferation, cell death, and oxidative stress genes. In addition, overlap was noted between genes affected by chronic arsenic exposure and those reported in the literature to be associated with caloric restriction and the metabolic syndrome. In particular, the gene for stearoyl-CoA desaturase (Scd1), which catalyzes the synthesis of monounsaturated fatty acids, was down-regulated by continuous arsenic treatment but up-regulated by in utero only treatment. Because Scd1 is important in the metabolic regulation of body weight, this response may explain the decrease in body weight gain seen in continuously exposed pups despite normal food consumption. Scd1 is implicated in hepatocarcinogenesis due to both environmental and genetic factors in rodents. Therefore, it and the genes it interacts with may be of key importance in the treatment-dependent tumor response reported here.

Purpose/Objective:

The purpose of this research is to evaluate age susceptibility to arsenic carcinogenesis in mice. This work provides MOA information in relation to comparative pathological and toxicogenomic results as a function of gestational/pubescent/post-pubescent stage exposures.

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Record Details:

Record Type: DOCUMENT (PRESENTATION/ABSTRACT)
Projected Completion Date: 04/20/2009
Record Last Revised: 07/09/2009
Record Created: 09/25/2008
Record Released: 09/25/2008
OMB Category: Other
Record ID: 199499

Organization:

U.S. ENVIRONMENTAL PROTECTION AGENCY

OFFICE OF RESEARCH AND DEVELOPMENT

NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB

ENVIRONMENTAL CARCINOGENESIS DIVISION

CELLULAR TOXICOLOGY BRANCH