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The Effect of Dibenzo[a,l]pyrene on the Thymus of Fetal Mice

The Effect of Dibenzo[a,l]pyrene on the Thymus of Fetal Mice. Vivian LaRonge Dr. William Baird’s Lab HHMI 2005. Cancer and the Environment. Most cancers linked to the environment. Lung and breast cancer most common for women. Hypotheses:.

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The Effect of Dibenzo[a,l]pyrene on the Thymus of Fetal Mice

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  1. The Effect of Dibenzo[a,l]pyrene on the Thymus of Fetal Mice Vivian LaRonge Dr. William Baird’s Lab HHMI 2005

  2. Cancer and the Environment • Most cancers linked to the environment. • Lung and breast cancer most common for women.

  3. Hypotheses: • In utero exposure to DBP results in Cyp1b1-mediated bioactivation and formation of DNA adducts in the thymus. • Presence of the AhR allele plays a important role in transplacental carcinogenesis by PAHs

  4. PAH • Polycyclic aromatic hydrocarbons • Environmental carcinogens formed by burning organic materials • Shape makes PAHs able to fit in DNA

  5. DBP • Dibenzo[a,l]pyrene is the most potent PAH and is an environmental pollutant and present in cigarette smoke. Fjord Region

  6. AhR • Aryl hydrocarbon receptor carries PAHs into the cell where they are metabolized. • Use Ah+ (“knock-in”) and Ah- (“knock-out”) mice • Ah+ allele dominant • Knock-in mice show higher risk

  7. aromatic hydrocarbon Protein Translation Aryl hydrocarbon receptor Cytoplasm AhR TNGC GTG XRE Gene (CYP1B1) Nucleus

  8. Cyp1b1 • Cytochrome P450 bioactivates many PAHs. • Cyp1b1 is specific to DBP. • Leads to tumor formation in many tissues

  9. Cyp Cyp

  10. Experimental Design

  11. Methodology • Carcinogen administered to mice by gavage 17th day of gestation. • Maternals and fetals sacrificed; thymus tissue removed.

  12. Isolate DNA from fetal thymus samples. Find DNA adducts if present, through use of 33P Postlabeling. Methodology cont.

  13. Pooling of fetal thymus samples • Pooled by maternal group, genotype

  14. STANDARD DBP HPLC elution profiles 1 mV = 1000 dpm

  15. Results • 2 day – no peaks • DNA adduct peaks revealed in the 6 day fetals. 0.2119978 pmol/mg Standard 6d-3 F 1,2 Ah +/-

  16. Future work • Detection of DNA adducts in the thymus of fetal and maternal mice on exposure to DBP at 2 days. • Address the mechanisms of trans-placental toxicity - Dr. Williams’ lab. • Facilitate approaches to prevention and therapy.

  17. Acknowledgements • Howard Hughes Medical Institute • National Institute of Health – CA90890 • Dr. Kevin Ahern • Dr. William Baird • Dr. Brinda Mahadevan • Dr. David Williams • Yu Zhen • Eric Brooks • Tamara Musafia

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