1. Sponsor Organization: NIH/CP

2. Project Title: 05352-13 METABOLIC AND PHARMACOLOGICAL DETERMINANTS IN PERINATAL CARCINOGENESIS

3. Project Focus:

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

4. Description:

Recent increases in certain childhood cancers call for continued research on perinatal carcinogenesis. We define this term broadly to include preconception, transplacental, and neonatal effects, as well as those of agents received in breast milk, and carry out research to characterize and understand the mechanisms of chemical carcinogenesis during these periods. Preconception carcinogenesis is a potentially important phenomenon, suggested particularly for men in epidemiological studies. We have investigated this in mice, especially with regard to effects of metals such as chromium (Cr). Characteristics of preconception carcinogenesis in animals suggests operation of a novel mechanism, and we have been pursuing, with some success, the hypothesis of deranged control of expression of the insulin-like growth factor II (IGFII) gene. Offspring of fathers exposed to either chromium or urethane show increased expression of IGFII in lungs, as assayed by Northern/slot blots with cDNA probes, ribonuclease protection assay, or quantitative reverse transcriptase (RT)-polymerase chain reaction (PCR). This important, ground-breaking new finding will be emphasized. Studies in transplacental carcinogenesis have included the drug, cisplatin, which initiated tumors of kidney, liver, and nervous system in fetal rats. We also tested the role of Ah locus phenotype on susceptibility of mouse fetuses to three polycyclic aromatic hydrocarbons, and confirmed that Ah responsiveness increased fetal tumorigenesis by 3-methylcholanthrene and 7,12-dimethylbenz[a]- anthracene (DMBA), but not by benzo[a]pyrene. Maternal responsiveness protected the fetuses uniformly. An important transplacental/neonatal trial has been started with the anti-AIDS drug, azidothymidine (AZT), a tissue-specific carcinogen in adult mice, now being administered to HIV-positive pregnant women. Genotoxic and oxygen stress effects of AZT will be studied. Chlorinated aromatic hydrocarbons, including polychlorinated bipenyls (PCBs), 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD), and dichlorodiphenyl trichloroethane (DDT) often occur in breast milk, and have been suspected in causation of human breast and lung cancers. We found, for the first time, TCDD to be a promoter of nitrosamine-initiated lung tumors in mice. For breast tumors in rats, TCDD at a nontoxic dose suppressed tumor development, but in an initiator-specific way: those initiated by DMBA were completely suppressed for 6 months, whereas those initiated by an aryl amine were unaffected.

5. References:

6. Inventory Category:

• Primary: Methods
• Secondary:

7. Inventory Subcategory:

• Primary: Hazard Identification
• Secondary:

8. Keywords for Experimental System/Species:

• Species:
  • mammal
  • human
• Study Type:
  • Laboratory Study
• Fate and Transport:

9. Keywords for Experimental Endpoints:

• Health Effect:
  • Carcinogenesis
• Hormonal Measures:
• Level Of Study:
• Chemistry Metabolism:
  • Tissue Residue
  • Ah Receptor
• Life Stage:
• Risk Assessment:

10. Chemical Agents:

• Dioxins
• PCBs
• Pesticides

11. Performing Institution:

• NCI INTRAMURAL PROGRAM

12. Contact:

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