1. Sponsor Organization: NIH/NIEHS

2. Project Title: 06556-04 BIOMARKERS OF DIOXIN-LIKE COMPOUNDS

3. Project Focus:

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

4. Description:

These studies will develop and validate sensitive mechanism-based molecular and biochemical markers of exposure, effect and/or susceptibility which will be specific for exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related halogenated aromatichydrocarbons (HAHs) and polycyclic aromatic hydrocarbons (PAHs). The experimental aims are based on the generally accepted concept that the Ah (aryl hydrocarbon) receptor is necessary, but not sufficient, for initiating the wide range of responses associated with exposure to TCDD and related compounds and that transcriptional activation of mRNA for cytochrome P-450 1A1 (CYP1A1) and CYP1A2 are the most sensitive known responses associated with exposure to these compounds. Aim 1 will develop and validate tissue biomarkers through assessing the responsiveness of maternal and fetal rat liver, placenta and lymphocytes to in vivo exposure to TCDD. The study will investigate the relationship between the tissue/body burden of TCDD and biomarker responses, which include: Ah receptor mRNA, nuclear bound "activated" Ah receptor, cytochrome P-450 1A1 (CYP1A1 and 1A2 in the liver) mRNA, protein and activities. Aim 2 will obtain preliminary data on the above biomarker responses in lymphocytes and placenta from current studies in human populations with characterized exposure to TCDD and related compounds. Aim 3 will investigate potential metabolic markers (probe drugs) of human exposure to TCDD and related compounds using precision-cut rat and human liver slices in dynamic organ culture. The responsiveness of rat and human liver to in vitro exposure to TCDD will be assessed through comparing tissue TCDD concentrations with the in vivo tissue biomarker responses measured in aim 1. l7B-Estradiol and caffeine metabolism will be initially investigated as potential metabolic markers of human CYP1A1 and CYP1A2, respectively. In the future, "probe drugs" such as these may be safely administered to human subjects to assess the selective induction of CYP1A1 and CYP1A2.

5. References:

6. Inventory Category:

• Primary: Methods
• Secondary:

7. Inventory Subcategory:

• Primary: Biomakers
• Secondary:

8. Keywords for Experimental System/Species:

• Species:
  • Mammal
  • Human
  • Rat
• Study Type:
  • In Vitro
  • In Vivo
• Fate and Transport:

9. Keywords for Experimental Endpoints:

• Health Effect:
  • Neurological
  • Reproductive
• Hormonal Measures:
  • Ah Receptor, Molecular
• Level Of Study:
• Chemistry Metabolism:
  • Tissue Residue
  • Cytochrome P450
  • Exposure Monitoring
• Life Stage:
• Risk Assessment:

10. Chemical Agents:

• Dioxins

11. Performing Institution:

• STATE UNIVERSITY OF NEW YORK AT BUFFALO

12. Contact:

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