Numerous findings have raised the level of national concern that chemicals found in the environment may have adverse effects on humans and wildlife. The Environmental Protection Agency's (EPA's) recent reassessment of dioxin toxicity concluded that body burdens of many individuals might exceed threshold levels that trigger developmental delays and hormonal changes. Additionally, this evaluation indicates that the dioxin-associated cancer risk is 10-fold higher than previous estimates. Environmental exposures have been implicated in contributing to gonadal tumors in eastern Maine softshell clams (M. arenaria); tumor prevalence as high as 40% has been observed in some feral populations. Tumor incidence has been correlated with the use of the herbicides 2,4 dichlorophenoxyacetic acid (2,4-D) and dioxin-contaminated 2,4,5-trichiorophenoxyactic acid (2,4,5-T). Epidemiological studies of women in the same geographical area document mortality rates from reproductive system cancers that are higher than the national average. These observations suggest that environmental exposures may contribute to the etiology of these cancers and to other reproductive effects. Understanding the molecular mechanisms by which tumors develop in the clam model may provide important information on the effect of chronic low-level environmental exposures and allow us to better extrapolate possible health risks to humans. Laboratory exposures established that bivalves accumulate dioxin, with the gonad serving as a reservoir. Dioxin exposure induced differential gene expression and both dioxin and herbicides had significant, negative impact on gametogenesis. The investigators have cloned a clam homologue to the vertebrate aryl hydrocarbon/dioxin receptor (AHR) that demonstrates structural similarity to human AHR. Continuation of these studies will focus on: 1) clam AHR characterization (e.g., ligand identification, protein-protein interactions, and biological activity); 2) further investigation of environmental toxicant impact on cell-cycle regulation pathways (e.g., stimulation of E3-mediated degradation of p53); and 3) short- and long-term laboratory exposures to herbicides and dioxin to evaluate effects on reproductive fitness.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES012066-10
Application #
6778390
Study Section
Special Emphasis Panel (ZRR1-CM-9 (03))
Program Officer
Heindel, Jerrold
Project Start
1993-12-16
Project End
2007-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
10
Fiscal Year
2004
Total Cost
$257,250
Indirect Cost
Name
University of Maine Orono
Department
Zoology
Type
Schools of Arts and Sciences
DUNS #
186875787
City
Orono
State
ME
Country
United States
Zip Code
04469
Walker, Charles W; Van Beneden, Rebecca J; Muttray, Annette F et al. (2011) p53 Superfamily proteins in marine bivalve cancer and stress biology. Adv Mar Biol 59:1-36
Muttray, Annette F; O'Toole, Teagan F; Morrill, Wendy et al. (2010) An invertebrate mdm homolog interacts with p53 and is differentially expressed together with p53 and ras in neoplastic Mytilus trossulus haemocytes. Comp Biochem Physiol B Biochem Mol Biol 156:298-308
Lindsay, S; Chasse, J; Butler, R A et al. (2010) Impacts of stage-specific acute pesticide exposure on predicted population structure of the soft-shell clam, Mya arenaria. Aquat Toxicol 98:265-74
Holbrook, Lauren A C; Butler, Rondi A; Cashon, Robert E et al. (2009) Soft-shell clam (Mya arenaria) p53: a structural and functional comparison to human p53. Gene 433:81-7
Butler, Rondi A; Kelley, Melissa L; Olberding, Kristen E et al. (2004) Aryl hydrocarbon receptor (AhR)-independent effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on softshell clam (Mya arenaria) reproductive tissue. Comp Biochem Physiol C Toxicol Pharmacol 138:375-81
Olberding, Kristen E; Kelley, Melissa L; Butler, Rondi A et al. (2004) A HECT E3 ubiquitin-protein ligase with sequence similarity to E6AP does not target p53 for degradation in the softshell clam (Mya arenaria). Mutat Res 552:61-71