1. Sponsor Organization: NIH/NIEHS

2. Project Title: 00834-24 EFFECTS OF CHLORINATED HYDROCARBONS ON MAMMALIAN SYSTEMS

3. Project Focus:

• Project Primary Focus: Human Health Effects
• Project Secondary Focus:

4. Description:

This study will examine in rodents and man the metabolism and potential toxicity of the proestrogenic pesticide methoxychlor 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, a TACE analog, used as anti-breast cancer agent, will serve as a model triphenylethylene. The importance of studying these compounds is: a) they represent structural analogs of several classes of pesticidal and non-pesticidal xenobiotic compounds and b) they are environmental estrogens and toxic to sexual development and reproduction. The compounds are metabolized by several routes, yielding estrogens and antiestrogens by one route and reactive intermediates (RIs) by another route. The RIs bind to neighboring proteins and some RIs also bind to proteins at distant sites. The various RIs are formed by different P450 enzymes. There are also differences in RIs stability and direction of migration. Our observation that methoxychlor binds covalently to thyroxine deiodinase, the key enzyme forming the active thyroid hormone (T3), stimulates novel tracks of investigation. We'll determine: (i) the trafficking pattern of the RIs, (ii) the reason(s) for specificity of acceptor protein for RI, (iii) whether binding of the RIs is toxic, i.e., does methoxychlor inhibit T3 synthesis and elicits hypothyroid effect, and (iv) how different P450s (in consort and alone) orchestrate the divergent routes of metabolism and how is the balance maintained. To diminish the use of animals, we'll develop a breast cancer cell line to merge metabolism capability with estrogen detection. This should facilitate the determination of whether a xenobiotic is an estrogen, antiestrogen, proestrogen, proantiestrogen or is inactive.

5. References:

6. Inventory Category:

• Primary: Models
• Secondary:

7. Inventory Subcategory:

• Primary: Basic Research
• Secondary:
  • Exposure And Risk Models

8. Keywords for Experimental System/Species:

• Species:
  • Mammal
  • Rodents
  • Human
  • Rat
• Study Type:
  • Laboratory Study
• Fate and Transport:

9. Keywords for Experimental Endpoints:

• Health Effect:
  • Reproductive
  • Molecular
• Hormonal Measures:
  • Hormone Receptors
  • Thyroid Hormones
• Level Of Study:
• Chemistry Metabolism:
  • Xenobiotic Metabolism
  • Cytochrome P450
• Life Stage:
  • Male
• Risk Assessment:

10. Chemical Agents:

• Chlorotriazines
• Pesticides
• Ddt, Methoxyvhlor,, Tamoxifen

11. Performing Institution:

• WORCESTER FOUNDATION FOR BIOMEDICAL RES

12. Contact:

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