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EDRI Federal Project Inventory:
62269-01a2 Metallotheonein and Cadmium Carcinogenesis in Rat Prostate
- Sponsor Organization: NIH/NCI
- Project Title: 62269-01A2 METALLOTHEONEIN AND CADMIUM CARCINOGENESIS IN RAT
PROSTATE
- Project Focus: HUMAN HEALTH EFFECTS
- Description: Although cadmium (Cd) is a proven carcinogen in rodents and may be a
"sufficient" carcinogen in men, themechanism of Cd-induced
carcinogenesis remains unknown. Additionally, while Cd is cytotoxic to
a wide spectrum oftissues in the body, its carcinogenicity is limited
to the prostate, testes and lungs. It has been postulated that
theexpression of the metal-binding protein, metallothionein (MT),
plays a role in determining tissue susceptibility to Cdtoxicity and
carcinogenicity. We, and others, have shown that rat ventral prostate
(VP) and testes, both target organs ofCd carcinogenesis, lack MT
expression. The aim of this proposal is to determine whether MT plays
a protective role inCd carcinogenesis. We hypothesize that "induced"
expression of MT in rat VP would render the gland resistant to
Cdcarcinogenicity. Using a transgenic animal approach, we shall
attempt to induce MT expression in rat VP. A chimericgene will be
synthesized by fusing the rat probasin (PB) promotor and 5'-flanking
region to a mouse MT coding regioncDNA (PB-MT construct). The PB gene
5'- flanking region contains two androgen responsive elements and a
sequencethat targets a transgene expression specifically to the
prostate of a transgenic animal. The expression of PB-MT will
heinduced in an androgen- receptor positive PC-3-cloned prostatic
cancer cell line (AR+ PC-3) transfected with thechimeric gene and,
later, in transgenic animals carrying the construct by androgen
activation. Alterations in cellular ortissue susceptibility to Cd
carcinogenicity after induction of MT expression will he assessed by
monitoring a set of "earlyor intermediate" biomarkers. Specifically,
these biomarkers are: 1) cytotoxicity, as measured by the expression
of a celldeath-associated gene (TRPM-2) and "internucleosomal DNA
fragmentation", 2) proliferation, as quantitated in situ bylevels of
histone-3 transcripts and proliferation cell nuclear antigen (PCNA),
3) genotoxicity as assessed by the degreeof nuclear DNA strand breaks
and DNA-protein formation, and 4) epithelial atypical hyperplasia, as
a morphologicalmarker of neoplastic development. To measure
tumorigenicity per se, tumor incidence will he enumerated
histologicallyand malignancy of the primary tumors will be assessed by
anchorage-independent growth, cellular ploidy and in vivotumor
formation efficiency in isogeneic hosts. Should our theory be proven,
we expect to observe either abolition ordelay in development of the
early or intermediate biomarkers of carcinogenesis, reduction of tumor
incidence, and/orreduced malignancy of the primary tumors formed in
the VPs of transgenic rats expressing MT, as compared to thosefound in
normal VPs. Data from these experiments are expected to yield
important information concerning the role ofMT in Cd tumorigenesis.
They should illuminate the mechanisms of prostatic carcinogenesis and
decipher the causes ofheavy metal toxicity.
- References:
- Category: MODELS
- Subcategory: BASIC RESEARCH
- Keywords for Experimental System/Species: LABORATORY STUDY
- Keywords for Experimental Endpoints: CARCINOGENESIS, TRANSGENIC MODEL
- Chemical Agents: CADMIUM
- Performing Institution: TUFTS UNIVERSITY MEDFORD
- Contact: CONTRACT PERSON: ELAINE C. LEE; BUILDING 31; 11A21; NATIONAL CANCER
INSTITUTE, NIH,BETHESDA, MD 20892-2590; 301-496-5515;
LEEE@OD.NCI.NIH.GOV
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