1. Sponsor Organization: NIH/NIEHS

2. Project Title: 25001-20 ROLE OF MUTAGENESIS IN CARCINOGENESIS

3. Project Focus:

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

4. Description:

Most chemical carcinogens induce DNA damage and are mutagenic at specific genetic loci; however, certain carcinogens (including the human carcinogens diethylstilbestrol (DES), asbestos, arsenicals, benzene and testosterone) usually do not induce gene mutations. We examined the ability of these chemicals to induce morphological transformation, gene mutations and chromo- some mutations in Syrian hamster embryo (SHE) cells in culture. Because androgenic and estrogenic compounds have been associated with cancer induction in animals and humans, we explored mechanistic studies of select naturally occurring and synthetically produced hormones. Previous studies showed that natural estrogens (17deltax-estradiol) and synthetic estrogen (DES) are capable of cell transformation of SHE cells in culture. The role of mutagenic changes (aneuploidy induction and DNA damage) in transformation by estrogenic compounds was studied. Testosterone, testosterone propionate, 17_- trenbolone and progesterone, which represent the main endogenous and synthetic androgens, and a progestin, were evaluated for possible cell transformation and genetic effects in SHE cells. Testosterone and testosterone propionate were less toxic than the other two steroids. Testosterone, testosterone propionate and progesterone induced morphological transformation of SHE cells with similar transformation frequencies. Most potent effects were observed with testosterone propionate. 17_-Trenbolone did not induce cell transformations at any dose tested. Transformation frequencies induced by testosterone, testosterone propionate and progesterone were less than one-half that induced by benzo[a]pyrene.None of these steroids induced significant increases in frequencies of chromosome aberrations or aneuploidy. Gene mutations were not observed for testosterone These steroids are also associated with carcinogenic activity in vivo,these in vitro findings provide a model and new insights into the study of the mechanisms of androgen- and progestin- induced cell transformation.

5. References:

6. Inventory Category:

• Primary: Models
• Secondary:

7. Inventory Subcategory:

• Primary: Basic Research
• Secondary:

8. Keywords for Experimental System/Species:

• Species:
  • Mammal
  • Hamster
• Study Type:
  • In Vitro
  • Laboratory Study
• Fate and Transport:

9. Keywords for Experimental Endpoints:

• Health Effect:
  • Carcinogenesis
• Hormonal Measures:
• Level Of Study:
• Chemistry Metabolism:
• Life Stage:
  • Embryo
• Risk Assessment:

10. Chemical Agents:

• Androgens/Anti-Androgens
• Diethylstilbestrol
• Estrogens/Anti-Estrogens

11. Performing Institution:

12. Contact:

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