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EDRI Federal Project Inventory:
60250-04 Neonatal DES Induced Uterine Dysplasia/Neoplasia
- Sponsor Organization: NIH/NCI
- Project Title: 60250-04 NEONATAL DES INDUCED UTERINE DYSPLASIA/NEOPLASIA
- Project Focus: EXPOSURE ASSESSMENT
- Description: When hamsters are healed neonatally with the synthetic estrogen,
dethylstibestrol (UES), their uteri consistent exhibita severe
hyperplastic/neoplastic response to estrogen in adulthood. One of two
alternatives working hypotheses shouldexplain this phenomenon: 1)
Direct Action The cellular physiology and/or composition of the
neonatal hamster uterusis directly and permanently altered by the DES
insult such that the adult organism overall proliferative response
toestrogen becomes atypical, or 2) Indirect Action Uterotrophic
activity is mediated by estrogen primarily through or inconjunction
with other unidentified factors, and neonatal DES treatment
permanently alters the level or functionalactivity of such factors.
Testing these hypotheses will begin (Specific Aim #1) by monitoring
the morphogenesis ofneonatal uteri from control and DES healed donot
animals that are transplanted into the contralateral cheek pouches
ofcontrol and DES-treated mature hosts that are ovariectomized and
estrogen-replaced. To confirm and extend thefindings (Specific Aim
#2), homotypic and heterotypic recombination of uterine stroma and
epithelium from control andDES-treated animals will be performed and
their morphogenesis will be studied: a) in vitro using media
supplementedwith uterine tissue extracts and/or serum from the same
host groups used in Specific Aim #1 and b) in vivo (within thecheek
pouch) using the same host groups as in Specific Aim #1. Because this
combination of approaches relies on few,if any, a prior assumptions
and accommodates both in vivo and in vitro observations, firm
conclusions should be reachedabout which alternative hypothesis is
most valid. Lastly (Specific Aim #3), we will test whether altered
expression ofknown regulatory genes is involved in the atypical
estrogen responsiveness of adult uteri in neonatally DES
treatedhamsters. We will begin with the c-myc c-tos and c-jun proto-
oncogenes plus the p53 anti-oncogene. Their expressionwill be probed
at the RVA and protein level as well as at the whole organ and cell
specific level using Northern blotanalysis, in situ hybridization,
immunoprecipitation/ Western blot analysis and immunohistochemistry.
Together thesestudies should contribute significantly to our long-term
objectives of 1) understanding the basic mechanisms wherebyestrogen
regulates uterine growth and morphogenesis and 2) identifying
mechanistic alterations that are responsible fordegeneration of this
process to the unregulated neoplastic state.
- References:
- Category: MODELS
- Subcategory: BASIC RESEARCH
- Keywords for Experimental System/Species: LABORATORY STUDY, IN VIVO, IN VITRO
- Keywords for Experimental Endpoints: PHYSIOLOGY, GROWTH
- Chemical Agents: ESTROGEN, DETHYLSTIBESTROL (DES)
- Performing Institution: WICHITA STATE UNIVERSITY
- Contact: CONTACT 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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