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EDRI Federal Project Inventory:
00834-21 Effects of Chlorinated Hydrocarbons on Mammalian Systems
- Sponsor Organization: NIH/NIEHS
- Project Title: 00834-21 EFFECTS OF CHLORINATED HYDROCARBONS ON MAMMALIAN SYSTEMS
- Project Focus: HUMAN HEALTH EFFECTS
- Description: This study will examine in rodents and man the metabolism and
potential toxicity of the proestrogenic pesticidemethoxychlor and of
one of its contaminants chlorotrianisene (TACE). Methoxychlor, used as
a substitute for DDT,contains numerous contaminants some of which are
proestrogenic and/or proantiestrogenic (e.g., TACE). Tamoxifen, aTACE
analog, used as anti-breast cancer agent, will serve as a model
triphenylethylene. The importance of studyingthese compounds is: a)
they represent structural analogs of several classes of pesticidal and
non-pesticidal xenobioticcompounds and b) they are environmental
estrogens and toxic to sexual development and reproduction. The
compoundsare metabolized by several routes, yielding estrogens and
antiestrogens by one route and reactive intermediates (RIs) byanother
route. The RIs bind to neighboring proteins and some RIs also bind to
proteins at distant sites. The various RIsare formed by different P450
enzymes. There are also differences in RIs stability and direction of
migration. Ourobservation that methoxychlor binds covalently to
thyroxine deiodinase, the key enzyme forming the active thyroidhormone
(T3), stimulates novel tracks of investigation. We'll determine: (i)
the trafficking pattern of the RIs, (ii) thereason(s) for specificity
of acceptor protein for RI, (iii) whether binding of the RIs is toxic,
i.e., does methoxychlorinhibit T3 synthesis and elicits hypothyroid
effect, and (iv) how different P450s (in consort and alone)
orchestrate thedivergent routes of metabolism and how is the balance
maintained. To diminish the use of animals, we'll develop abreast
cancer cell line to merge metabolism capability with estrogen
detection. This should facilitate the determinationof whether a
xenobiotic is an estrogen, antiestrogen, proestrogen, proantiestrogen
or is inactive.
- References:
- Category: MODELS
- Subcategory: BASIC RESEARCH, EXPOSURE AND RISK MODELS
- Keywords for Experimental System/Species: HUMAN, MAMMALIAN (RAT), LABORATORY
- Keywords for Experimental Endpoints: MALE, HORMONE RECEPTORS, THYROID HORMONES, XENOBIOTIC METABOLISM,
CYTOCHROME P450, TOXICOKINETICS, REPRODUCTION (INCLUDING
DEVELOPMENTAL), MOLECULAR
- Chemical Agents: DDT, METHOXYCHLOR (72-43-5), CHLOROTRIANISENE (TACE), TAMOXIFEN
- Performing Institution: WORCESTER FOUNDATION FOR BIOMEDICAL RES
- Contact: CONTACT PERSON: DR. HEINDEL, NIEHS, P.O. BOX 12233, RTP, NC. 27709,
919-541-0781,HEINDEL_J@NIEHS.NIH.GOV
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